Method of preparing a radiodiagnostic comprising a gaseous radionuclide, as well as a radionuclide generator suitable for using said method

ABSTRACT

The invention relates to a method of preparing a radiodiagnostic comprising a gaseous radionuclide formed by radioactive decay of a parent nuclide, by eluting with a suitable eluent the radioactive daughter nuclide from the parent nuclide provided ionically on a carrier, by using as a carrier for the parent nuclide ions a membrane, in particular an ion exchange membrane, past which the eluent is made to flow. 
     The invention further relates to a radionuclide generator suitable for using said method.

The invention relates to a method of preparing a radiodiagnosticcomprising a gaseous radionuclide formed by radioactive decay of aparent nuclide, by eluting with a suitable eluent the radioactivedaughter nuclide from the parent nuclide provided ionically on acarrier.

Such radiodiagnostics are intended in particular for lung functionexamination and regional blood circulation measurements. Examples ofgaseous radionuclides are radioactive noble gases which can be elutedinter alia with gaseous eluents, for example, oxygen or air, and arethen suitable for pulmonary ventilation studies. For example, incombination with lung perfusion scintigraphy, lung defects, likepulmonary embolies, obstructions in the bronchi and the like, can inthis manner be detected and localised in a simple manner.

A radioactive noble gas to be considered for such an examination isradioactive krypton, in particular krypton-81m (^(81m) Kr). Krypton-81mwhich has been available for a few years already, has favourableradiation characteristics, for example, a half life of only 13 secondsand the absence of beta rays. Due to the many favourable properties ofkrypton-81m, physical and chemical as well as physiological, there ishence an increasing interest for the use of this radionuclide inradiodiagnostics, in particular for pulmonary ventilation studies andregional blood circulation measurements. However, krypton-81m may alsobe used for example for lung perfusion scintigraphy, althoughtechnetium-99m compositions are often preferred for such applications.It may be desirable for such applications to have the disposal of aliquid radiodiagnostic. For this purpose liquid eluents may be used, forexample, a 5% glucose solution, to elute krypton-81m from the parentnuclide, i.c. rubidium-81 (⁸¹ Rb), provided on a carrier.

A device in which a radioactive daughter nuclide is formed byradioactive decay of a parent nuclide and can then be eluted is termed aradonuclide generator. Various generators are known for generatingradiodiagnostics comprising gaseous radionuclides, in particularkrypton-81m. Such generators should be suitable for elution with air oroxygen, after which the gas enriched with krypton-81m must be inhaledimmediately by the patient in connection with the short half life of theradionuclide. By situating suitable detection apparatus, for example, agamma camera, near the patient during said inhalation, a study can bemade of, for example, the patient's lung function. In the systems mostin use the parent nuclide is provided on an adsorption agent in a columnin which during the elution the gaseous eluent is allowed to flowthrough the column. As adsorption agents for the column are to beconsidered ion exchanging resin beads and zirconium phosphate, forexample, as indicated in publications of Mostafa et al (J. Nucl. Med.24, 157-159, 1983) and of Beyer et al (Int.J.Appl.Radiat.Isot. 35,1075-1076, 1984). During the elution the gaseous daughter nuclide, i.c.krypton-81 m, is entrained by the gas flow while the parent nuclide,i.c. rubidium-81, must remain behind on the column. However, as a resultof the presence of a pressure drop over the packed column, the elutionefficiency is detrimentally influenced and in certain circumstances mayeven be some tens of percents lower than the maximally achievable yield.An improvement can be achieved by using a humidifying system to humidifythe gaseous eluent prior to elution; also in the system described byMostafa et al a humidifier is used. Apart from the fact that an elutionefficiency which is satisfactory in every respect is not yet achieved byhumidifying the air or oxygen, other disadvantages are introduced by theuse of a humidifier: the system becomes more complicated and the purity(asepsis) of the air or oxygen to be used for elution may becompromised. The elution efficiency can be considerably improved bycausing the gaseous eluent to flow through the adsorption column at alower rate. However, the residence time of the eluate, i.e. of the airor oxygen enriched with radionuclide, in the supply lines to the patientthen increases, as a result of which the loss of radionuclide due toradioactive decay also increases.

In the above publication of Beyer et al a new type of ⁸¹ Rb-^(81m) Krgenerator is introduced in which a certain type of foil in which theparent nuclide has been provided is used instead of a column loaded withrubidium-81. The attempt of providing the parent nuclide in the foil ina simple manner has obviously not been successful. A system suitable forelution can be obtained only by implanting rubidium-81 ions into theplastic foil by means of an accelerator. It will be obvious that such asystem is highly impractical and is to be considered to be of atheoretical interest only.

In order to avoid the above problems which are associated with thepressure drop over the packed column, a so-called paper generator hasbeen developed: Nucl.Instr. Methods 156(1978), 369-373. In thisgenerator winded filter paper is used as a carrier for the parentnuclide and is accommodated in a cylinder. The operation of thegenerator is based upon the absorption of a rubidium-81-containingaqueous solution by the filter paper and on the diffusion of the desireddaughter nuclide krypton-81m to the passing air or oxygen used as aneluent. This system is less universal than the system using a packedcolumn because in the first-mentioned system liquid cannot be used as aneluent in practice. Moreover, the parent nuclide in the described papergenerator is much more weakly bound to the carrier, which increases therisk of the presence of traces of rubidium-81 in the radiodiagnostic (⁸¹Rb breakthrough).

It is the object of the invention to provide a method of preparing aradiodiagnostic comprising a gaseous radionuclide in which the abovedisadvantages do not occur. According to the present invention thisobject can be achieved by using in the method described in the openingparagraph, in which the radioactive daughter nuclide, in particularkrypton-81m, is eluted with a suitable eluent from the parent nuclide,in particular rubidium-81, provided ionically on a carrier, as a carrierfor the parent nuclide ions a membrane, in particular an ion exchangemembrane, past which the eluent is made to flow.

It has been found that when such a membrane is used as a carrier for theparent nuclide, the disadvantages of the use of a packed column as acarrier are avoided, while nevertheless the good properties of such acolumn are maintained. In this manner the system according to theinvention is pressureless because during the elution the eluent may becaused to flow past the membrane. In this manner an elution efficiencycan be reached which is considerably higher and less influenced by theelution rate than when a packed column is used; this will be illustratedin greater detail in the examples. Furthermore, when air or oxygen isused as an eluent, humidifying hereof has become superfluous. The rigidbond of the parent nuclide ions in the membrane matrix reduces thepossibility of a breakthrough of undesired nuclides compared with thepaper generator described hereinbefore. Finally, the method according tothe invention is universally applicable because both gaseous eluents,like air or oxygen, and liquid eluents, like a glucose solution oranother suitable eluting liquid, may be used in the elution.

It has been found surprisingly that an equally high elution efficiencyis obtained by making the eluent to flow past one side of the membraneon which the parent nuclide has been provided, instead of past bothsides. The great advantage hereof is that in this manner the generatormay have a simpler construction, as will be described hereinafter, whilealso the possibility of a breakthrough into the eluent and of acontamination of the eluent with the parent nuclide is reduced.

The invention also relates to a method of preparing a radiodiagnosticcomprising a gaseous radionuclide, which method comprises in addition tothe elution process the loading process in which, prior to the elution,the membrane to be used according to the invention is loaded with parentnuclide by causing a solution of parent nuclide ions to pass through themembrane; the parent nuclide remains behind in the membrane matrix.Compared with a granular adsorption agent in a column, a membrane canbetter be handled, so that the manipulations which are necessary for theloading operation can be carried out more easily.

The method of preparing the radiodiagnostic is preferably carried out insuch manner that the membrane is loaded by causing the ion solution topass through the membrane via successively upper surface and lowersurface, and that the elution is carried out afterwards by making theeluent to flow past the lower surface of the membrane. In this manner itis ensured that a breakthrough of parent nuclide does not occur. Inother words, by carrying out the loading and the elution in this manner,parent nuclide is not found in the eluate, i.e. in the resultingradiodiagnostic, irrespective of the rate at which the elution iscarried out. In addition, in this manner optimum use is made of a secondproperty of the membrane: the filtering activity. Should any undesiredparticles ("particulate matter"), like dust particles, arrive on themembrane during the loading operation, than these particles can neverreach the eluate in this manner.

The invention further relates to a radionuclide generator, suitable forusing the above method of preparing a radiodiagnostic comprising agaseous radionuclide, According to the invention the radionuclidegenerator is characterised in that the generator comprises a membrane,optionally supported by a grid, in particular an ion exchange membrane,which is accommodated in a room enclosed by a generator housing havinginlet and outlet apertures in such a manner that an eluent can be madeto flow through the room past the membrane. The small size of themembrane enables an extremely compact construction of the generator. Asa result of this the lead shielding jacket may be kept small and hencecomparatively light. This facilitates transport, which means a greatadvantage with respect to the logistic problems which frequently occurwith shortliving radioactive material. Moreover, the handling of thegenerator in the clinic is facilitated by the low weight. In addition,the extremely small size enables the administration of a highly-activebolus, for example, a krypton-81m bolus, in a very small volume, so thatthe possibilities for using the generator are expanded. The gridoptionally to be used for supporting the membrane is preferablymanufactured from a radiation-resistant and rigid material, for example,stainless steel or chromiumplated nickel. The positioning of themembrane in the room should be adapted to the inlet and outlet aperturesfor the eluent in such a manner that during the elution said eluent canreadily be made to flow past the membrane.

In a practical embodiment the radionuclide generator is constructed insuch a manner that the membrane is circumferentially sealingly attachedin the generator housing and so divides the room into two parts, onepart of said room comprising an inlet aperture in the generator housingfor the solution to be used for loading the membrane, the other part ofthe room comprising an outlet aperture for the loading solution. Theseprovisions permit of loading the membrane with parent nuclide in theroom itself, so inside the generator housing. For this purpose theloading solution, i.e. the solution of the parent nuclide ions, isprovided through the inlet aperture of the generator housing into theroom, is pumped or sucked through the membrane and discharged on theother side of the membrane through the outlet aperture. The generatorthen is ready for use, that is to say, ready for elution. If desired,the resulting generator can be sterilised in a very simple manner, forexample, by autoclaving.

In a certain embodiment which will be described in greater detailhereinafter the radionuclide generator according to the invention isconstructed in such a manner that, in addition to the inlet and outletapertures, the generator housing comprises a closable by-pass whichinterconnects the parts of the room. Upon loading the membrane theby-pass is closed so that the loading solution must pass through themembrane. During elution the by-pass is opened so that the eluent ismade to flow past the membrane via inlet aperture, by-pass and outletaperture. A correct positioning of the membrane with respect to theapertures in the generator housing and of the bypass favours an optimumelution.

In a preferred embodiment which differs from the embodiment describedhereinbefore the radionuclide generator according to the invention isconstructed in such a manner that said one part of the room comprisesthe said inlet aperture in the generator housing intended for theloading solution and the other part, which is separated from said firstpart by the membrane, comprises an outlet aperture intended for theeluent, which aperture is positioned in the generator housingapproximately oppositely to the outlet aperture for the loadingsolution. Said latter aperture also serves as an inlet aperture for theeluent (bifunctional aperture). Structurally this construction issimpler than the construction of the generator described hereinbefore,while in addition the filtering properties of the membrane are used;this will be described in greater detail hereinafter. Another advantagepresented by this embodiment is the possibility of allowing the outletapertures of loading solution and eluent not to coincide. As a result ofthis, the outlet aperture for the eluent is not "contaminated" withparent nuclide during the loading operation, which further reduces therisk of the presence of parent nuclide in the eluate. Moreover, thisembodiment presents the possibility of positioning the apertures in thegenerator housing in such a manner that the loading process isfacilitated and the elution is optimised.

It has further proved of advantage to dimension the radionuclidegenerator in the last preferred embodiment so that the membrane dividesthe room in such a manner that the volume of the one part, provided withsaid inlet aperture for the loading solution, is small with respect tothe volume of the other part provided with the outlet aperture for theeluent and the bifunctional aperture. By minimising the volume of thefirst-mentioned room, i.e. making it as small as possible, the elutionefficiency can still be further improved.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will now be described in greater detail hereinafter withreference to the ensuing specific examples and illustrated withreference to the accompanying drawings. In these drawings,

FIGS. 1 and 2 are diagrammatic longitudinal sectional views of twodifferent embodiments of radionuclide generators according to theinvention; and

FIGS. 3, 4 and 5 are graphs showing the elution efficiencies of thegenerators shown; these Figures will be described with reference to thespecific examples.

The radionuclide generator shown in the longitudinal sectional view ofFIG. 1 comprises a membrane 11 which is circumferentially sealinglyattached in the generator housing 10 and which is supported by a metal(chromiumplated nickel or stainless steel) grid 12. A Bio-Rex® cationexchange membrane is used as a membrane. The membrane divides the roomenclosed by the generator housing into two parts, one part 13 providedwith an inlet aperture 14 for the loading solution and the other part 15provided with an outlet aperture 16 for said loading solution. Thegenerator shown further comprises bypass 18 which can be closed (at 17)and which interconnects the parts 13 and 15. Upon loading the generatorwith parent nuclide rubidium-81, a solution of rubidium-81 ions (⁸¹Rb³⁰) is introduced at aperture 14, pumped through the membrane anddrained at outlet aperture 16, while the bypass is closed at 17. Duringelution of the loaded generator the bypass is opened at 17, after whichair is made to flow past the membrane as an eluent via aperture 14,bypass 18 and aperture 16. In another experiment described in Example IIthe elution is carried out in such a manner that the bypass is uncoupledat 19 and the generator housing is closed at 4 and 17, after which theair is made to flow past the membrane via the apertures 19 and 16.

The radionuclide generator shown in the longitudinal sectional view inFIG. 2 has the following internal dimensions: approx. 20 mm×approx. 15mm×approx. 1 mm. The generator comprises the same membrane 11 which isattached in the housing 20 and is supported by a grid 12 and whichdivides the room within the housing into two parts 21 and 22, one part(21) of which has a minimum volume. Part 21 comprises an inlet aperture23 for the loading solution, part 22 comprises an outlet aperture 24 forthe eluent and a bifunctional aperture 25 which upon loading serves fordraining the loading solution and during elution serves for introducingthe eluent. Upon loading the FIG. 2 generator with rubidium-81 as aparent nuclide the solution comprising the parent nuclide ions isintroduced at aperture 23 and pumped through the membrane. Sinceaperture 24 is closed, the solution leaves the generator via aperture25. During the elution the aperture 23 is closed, after which theelution is carried out with air via apertures 25 and 24.

EXAMPLE I Elution of the generator shown in FIG. 1 via 14-18-16

The generator shown in FIG. 1 is eluted via inlet aperture 14, bypass 18and outlet aperture 16 using air as an eluent. The krypton-81m activityis measured at different flow rates of the air in an arrangementconventionally used for this purpose and consisting of a Ge/Li detectorcoupled to a multichannel analyser. Comparison is made with a knowngenerator having an adsorption column packed with an ion exchange resin(Dowex® 50 W-X8; 100-200 mesh). For measuring the flow rate a flowmeteris connected at the end of the system. Both generators, the generatorshown in FIG. 1 and the known generator, are loaded with rubidium-81from the same loading solution and with the same loading system. Becausethe known generator has to be eluted with moist air to obtainreproducible values, the generator according to the invention is alsoeluted with the same moist air; this is not necessary but it enables abetter comparison of the results. All the radioactivity measurementshave been corrected for radioactive decay. The results are recorded inthe graphs of FIG. 3. In the graphs the elution efficiency Y (% yield inthe measuring position) is plotted against the flow rate v of the airflow in ml/min. From the obtained curves it appears that the yield ofkrypton-81m when using the generator "A" according to the invention asshown in FIG. 1 is 10 to 15% higher than when using the known generator"Z". Moreover, a much higher flow rate can be achieved.

EXAMPLE II Elution of the generator shown in FIG. 1 via 19-16

After uncoupling the bypass 18, the air flow is now introduced into thegenerator at 19, is made to flow past one side of the membrane and isthen exhausted from the generator at 16. Whereas in the experimentsdescribed in Example I a slight breakthrough of ⁸¹ Rb is observedoccasionally, the eluate, i.e. the air enriched with krypton-81m, is nowentirely free from parent nuclide contamination. The experiments areotherwise carried out as described in Example I. The results arerecorded in the graphs of FIG. 4, again in comparison with the knowngenerator having a packed column. The elution efficiency Y for thegenerator according to the invention "B" is surprisingly high, evenhigher than upon elution with the known generator "Z".

EXAMPLE III Elution of the generator shown in FIG. 2 via 25-24

The generator shown in FIG. 2 is eluted with air via 25-24. The eluateis entirely free from parent nuclide, while, as appears from the graphicresults shown in FIG. 5, the elution efficiency Y equals the efficiencyobtained according to example I. The difference in efficiency betweenthe generator according to the invention "C" shown in FIG. 2 and theknown generator "Z" having a packed column is remarkable.

We claim:
 1. A method or preparing a radiodiagnostic including a gaseousradioactive daughter nuclide formed by radioactive decay of a parentnuclide, the method comprising the step of eluting, with an eluent, theradioactive daughter nuclide from the parent nuclide, the parent nuclidebeing provided ionically on an ion exchange membrane, past which theeluent is made to flow.
 2. A method as claimed in claim 1 of preparing aradiodiagnostic including krypton-81m formed by radioactive decay ofrubidium-81, the method comprising the step of eluting said radionuclidefrom the rubidium-81, the rubidium-81 being provided ionically on an ionexchange membrane, past which the eluent is made to flow.
 3. A method asclaimed in claim 1, characterized in that the elution is carried out bycausing the eluent to flow past one side of the membrane on which theparent nuclide has been provided.
 4. A method as claimed in claim 2,characterized in that the elution is carried out by causing the eluentto flow past one side of the membrane on which the parent nuclide hasbeen provided.
 5. A method as claimed in any of the claims 1-4,characterized in that, prior to the elution, the membrane is loaded withparent nuclide by passing a solution of parent nuclide ions through themembrane, the parent nuclide remaining behind in the membrane matrix. 6.A method as claimed in claim 5, characterized in that the membrane is bycausing the ion solution to pass through via successively an uppermembrane surface and a lower membrane surface and that afterwards theelution is carried out by making the eluent to flow past the lowermembrane surface.
 7. A radionuclide generator suitable for using themethod as claimed in claim 1, characterized in that the generatorcomprises an ion exchange membrane, optionally supported by a grid,which is accommodated in a room enclosed by a generator housingcomprising inlet and outlet apertures, in such a manner that an eluentcan be made to flow through the room past the membrane.
 8. A generatoras claimed in claim 7, characterized in that the membrane iscircumferentially sealingly attached in the generator housing and inthis manner divides the room into two parts, one part of said roomcomprising an inlet aperture in the generator housing for the solutionto be used for loading the membrane, the other part of the roomcomprising an outlet aperture for the loading solution.
 9. A generatoras claimed in claim 8, characterized in that, in addition to the inletand outlet apertures, the generator housing comprises a closable by-passwhich interconnects the parts of the room.
 10. A generator as claimed inclaim 8, characterized in that said one part of the room comprises theinlet aperture in the generator housing intended for the loadingsolution and the other part, which is separated from said first part bythe membrane, comprises an outlet aperture intended for the eluent, saidoutlet aperture being positioned in the generator housing approximatelyoppositely to the outlet aperture for the loading solution, said latteraperture equally serving as an inlet aperture for the eluent such thatthe aperture is bifunctional.
 11. A generator as claimed in claim 10,characterized in that the membrane divides the room in such a mannerthat the volume of the one part provided with said inlet aperture forthe loading solution is small with respect to the volume of the otherpart provided with the outlet aperture for the eluent and thebifunctional aperture.